Hepatic disease can take a wide variety of forms including, but not limited to, necrosis, steatosis, fibrosis, and cholestatis. Other forms of liver disease can result from the ingestion of hepatotoxic medicines such as chemotherapy and cancer drugs, antibiotics, analgesics, antiemetics, and other medications. Also, alcohol and drug abuse are well known causes of liver disease. Typical causes of hepatic disease include, but are not limited to, viral and alcoholic hepatitis, Wilson's disease, hemochromatosis, steatosis, and nonalcoholic steatohepatitis (NASH).
Hepatic fibrosis is a common aspect of many, if not all, hepatic diseases and is defined as the formation of scar tissue in the liver. The scarring develops as the liver attempts to repair cellular damage induced by the ingestion of hepatotoxins, as a consequence of chronic liver inflammation, or as a consequence of physical insult. Hepatic fibrosis may also result as a consequence of surgical intervention and hepatotoxic drug therapy, i.e., liver replacement or repair or chemotherapy. In many cases, hepatic fibrosis produces permanent scarring of the hepatic tissue, a condition commonly referred to as cirrhosis.
Recent studies have disclosed that adenosine plays a role in the development and progression of hepatic fibrosis. Chunn et al. (2006) Am. J. Physiol Lung Cell Mol Physiol, 290(3):L579-87, detected increased hepatic fibrosis in adenosine deaminase (ADA) deficient mice. The mice utilized by Chunn et al. are genetically engineered to possess partial ADA enzyme activity and thereby accumulate adenosine of a prolonged period of time.
Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A1, A2A, A2B, and A3, all of which modulate important physiological processes. Of the various receptors, A2B adenosine receptors have been shown to modulate the synthesis and release of angiogenic factors and inflammatory cytokine and chemokines and are believed to be most significantly involved in inflammatory conditions via their connection to mast cell activation, vasodilation, and regulation of cell growth (See Adenosine A2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148-153).
Surprisingly, it has now been found that A2B adenosine receptor antagonists are also useful in the prevention and treatment of hepatic disease. Accordingly, it is desired to provide a method of treating and/or preventing hepatic disease by administration of compounds that are potent, fully or partially selective, A2B antagonists, i.e., compounds that inhibit the A2B adenosine receptor.